Kidney allograft rejection is characterized by an intense cellular immune response as reflected, in part, by marked infiltration of the graft with T cells, B cells, and macrophages. These immune responses are amplified by the production of proinflammatory cytokines and chemokines. In clinical transplantation, immunosuppressive agents block immune cell growth and function and thereby preserve allograft function. This blockade, however, is nonspecific and results in suppression of responses beneficial to the host, such as the immune response to infections and the clearance of tumor cells. Moreover, the non-specific immunotherapy is incompletely effective; most kidney allografts are eventually rejected. Thus, research is necessary to identify better and more specific immunotherapies to improve efficacy and to limit recipient complications. In previous studies, we used a mouse kidney transplantation model to characterize the cellular and molecular determinants of rejection. This model displays evidence for both an acute rejection response and a chronic response. These animals survive for prolonged periods of time in the absence of immunosuppression. Associated with prolonged survival, we found that the T cells infiltrating the grafs down-regulate the expression of their antigen specific T cell receptor (TCR). Using this model, we have shown that the absence of either MHC class I or II antigens modestly alters the acute rejection response, but only minimally influences chronic rejection (CR). We recently found that absence of both MHC class I and II antigens ameliorated CR development. Thus, mouse kidney transplants provide a useful animal model to study the molecular and cellular events of acute and chronic rejection. The aims of our lab are: (1) To characterize the requirement and location of donor MHC expression and determine if and how it alters immune responses to the graft. (2) To identify whether novel anti-fibrotic therapies might ameliorate chronic allograft rejection in the mouse model. (3) To determine the mechanism of TCR down-regulation and determine whether purposeful induction of TCR down-regulation may prolong allograft survival.